title: Pharmacological modulation of mGluR7 with AMN082 and MMPIP exerts specific influences on alcohol consumption and preference in rats.
abstract: Growing evidence supports a role for the central nervous system (CNS) neurotransmitter L-glutamate and its metabotropic receptors (mGluRs) in drug addiction in general and alcohol-use disorders in particular. Alcohol dependence, for instance, has a genetic component, and the recent discovery that variations in the gene coding for mGluR7 modulate alcohol consumption further validates involvement of the L-glutamate system. Consequently, increasing interest emerges in developing L-glutamatergic therapies for the treatment of alcohol abuse and dependence. To this end, we performed a detailed behavioral pharmacology study to investigate the regulation of alcohol consumption and preference following administration of the mGluR7-selective drugs N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082) and 6-(4-Methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). Upon administration of the allosteric agonist AMN082 (10 mg/kg, i.p.) in rats, there was a significant decrease in ethanol consumption and preference, without affecting ethanol blood metabolism. In contrast, mGluR7 blockade with MMPIP (10 mg/kg, i.p.) showed an increase in alcohol intake and reversed AMN082's effect on ethanol consumption and preference. Both mGluR7-directed pharmacological tools had no effect on total fluid intake, taste preference, or on spontaneous locomotor activity. In conclusion, these findings support a specific regulatory role for mGluR7 on alcohol drinking and preference and provide evidence for the use of AMN082-type drugs as potential new treatments for alcohol-use disorders in man.
authors.affiliation: Faculty of Biology and Preclinical Medicine, Laboratory of Molecular & Cellular Neurobiology, University of Regensburg, Universitätsstraße 31, Regensburg, Germany. amine.bahi@biologie.uni-regensburg.de
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.forename: Katharina
authors.initials: K
authors.lastname: Fizia
authors.forename: Monika
authors.initials: M
authors.lastname: Dietz
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Flor
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D000431:Ethanol / Q000378:metabolism; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012439:Saccharin / Q000494:pharmacology; D012646:Self Administration; D013549:Sweetening Agents / Q000494:pharmacology; D013649:Taste / Q000187:drug effects
chemical_list: C553164:6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazonolo(4,5-c)pyridin-4(5H)-one; D001559:Benzhydryl Compounds; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; D013549:Sweetening Agents; C102719:metabotropic glutamate receptor 7; D000431:Ethanol; D011803:Quinine; D012439:Saccharin